Injury or trauma to the knee, hip, or ankle is a well-documented contributor to premature onset of joint degeneration and osteoarthritis (OA). Nuclear factor kappa B (NF-?B) is a transcription factor that has early involvement in post-traumatic OA by activating genes involved in extracellular matrix catabolism and joint inflammation. Increased NF-?B activity has also been implicated in the development of pain following joint injury and other musculoskeletal pathologies. Despite the availability of numerous compounds that inhibit NF-?B, pharmacologic inhibition of NF-?B via systemic administration or even local delivery to the joint has not been successful in the treatment of OA. We hypothesize that intra-articular delivery of NF-?B antagonists from a safe, sustained-release carrier (silk) will have value in attenuating pain related sensitivities, joint dysfunction, and progressive joint pathology in a non-surgical, intra-articular fracture model of OA. We have previously identified a strong correlation between NF-?B activity and pain-related sensitivity in a model of inflammatory joint injury using the NF-?B-luciferase reporter mouse. Here, we will similarly track NF-?B activity, but in a mouse model of closed tibial fracture as a non-surgical model of joint injury which is known to progress to OA. In Specific Aim 1, we will evaluate the temporal and spatial development of NF-?B activity, pain- related sensitivities, and joint dysfunction in mice following intra-articular fracture out to 8 weeks. We will identify relationships between systemic and local NF-?B activation, patterns for sensitivity, gait and weight- bearing, and arthritis progression following joint fracture. Results will identify ?therapeutic windows? for timing of intra-articular drug delivery in Specific Aim 3. In Specific Aim 2, we will optimize silk fibroin microparticle depots for sustained release of two small molecule NF-?B inhibitors, SC-514 or PHA-408. We have previously demonstrated increased residence times for silk fibroin microparticles when delivered to the joint space, but have not incorporated a drug for sustained release. Silk fibroin microparticles (10-60 microns) will be fabricated specific to each NF-?B inhibitor, and tested to verify high drug loading and sustained release out to 4 weeks. In Specific Aim 3, we will evaluate if a single, intra-articular injection of SC-514 or PHA-408-loaded silk fibroin microparticles can attenuate NF-?B activation, pain-related sensitivities, joint dysfunction, and joint pathology after intra-articular fracture. Intra-articular injections of drug-loaded microparticles will be administered to the injured limb at either early or late times after injury, with longitudinal monitoring of effects on NF-?B activation, pain-related sensitivities, joint dysfunction and arthritis development. Results will reveal whether either compound, and at which time, can modulate defined outcome measures of arthritis symptoms and/or pathology progression in this model of OA. This work will establish a safe, sustained release strategy for the local treatment of OA that can advance utility for an entire class of small molecule NF-?B antagonists with a high likelihood for treating pathology and/or pain development in patients with OA.